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Last Updated

06 May 2003

Source: Newsday, May 6, 2003

A Chinese Lab's Race To ID And Halt SARS

Politics and rivalry mix with research

By Laurie Garrett, Staff Correspondent

Beijing -- In a dingy four-story building on a dark alley in this city's poorest district, 40 scientists toil through the day and night in the quest to understand and defeat the SARS virus.

They know other researchers around the globe have greater resources, and all are essentially competing, aiming to be first to identify the virus' Achilles heel. And they know that their work is sensitive in a country where the Communist Party leadership has been embarrassed after insisting for months that no such disease was present.

At 9 p.m. on Saturday, scientists here at the Viral Disease Control lab were prowling the unlit halls, egging one another on with jokes and animated arguments over every facet of the strange coronavirus that has been identified as the cause of severe acute respiratory syndrome. The dusty hallways are lined with ancient centrifuges and freezers full of microbes.

A high-safety BioSafety Level 3 lab is on one side of the hall; until six weeks ago, scientists worked there on HIV. Now researchers wear containment suits and work under stringent infection control conditions to study SARS.

Most of the building's labs are more modest facilities, reminiscent of college biology laboratories in the United States. There is a scarcity of computers.

The scientists appear to rely on high levels of energy and spurts of late night inspiration. They spent Saturday digesting two newly published genetic analyses of the SARS virus, as determined by teams in British Columbia and the United States. By the time the group gathered at 4 p.m. for their daily meeting, virologist Bi Shengli had circled stretches of the 29,751 genetic bits of information that constitute the SARS genome, having found some interesting correlations with various known animal viruses.

For weeks Bi had been racing to sequence the genome, only to learn Saturday that he'd been beat.

Bi heard on April 11 that the genome had been identified and would be posted on the Internet. "I go fast to the Net and see Canada has a large computer with the genome in it. Oh! I put my eye on the computer screen all day. I'm happy. I take some wine and say, 'Congratulations, guys!'" Bi recounts, lifting a glass of red wine. "Then I thought, 'OK, if you know the sequence, I don't need a large sample'" of SARS-contaminated blood or tissue for avenues of research that might pin down the virus' origins.

For starters, Bi realized he could use the genetic sequence information to amplify minute quantities of the virus into vast amounts for analysis, using a method called PCR, or polymerase chain reaction. "I am still in the game, but I must work quickly," he says with a wink.

In the laboratory nobody wears a mask, many scientists chain smoke, and they joke that tobacco smoke kills SARS. But outside the lab, the syndrome is no joking matter. Yesterday China's cumulative SARS caseload reached 4,280, with 206 dead. Beijing's share of that hit 1,897 cases, with 103 dead. Beijing authorities say the coming two weeks will be decisive: if China cannot push the epidemic into a downturn, SARS will become a permanent feature on the nation's disease landscape.

Other laboratories have reported disturbing findings in recent days. Chinese University scientists in Hong Kong said the virus is rapidly mutating, and already four separate strains are infecting patients in that region. A German research team announced that the virus can withstand disinfecting soap. And evidence has mounted that SARS cases are transmitted through exposure to contaminated feces. The World Health Organization announced that the virus can survive outside the body, in feces, for hours, raising the possibility that unclean hands might carry it to surfaces such as doorknobs and banisters.

Bi shrugs off the fear. He professes to be "just playing," having fun in his laboratory.

But such "play" has accomplished some important things, including identifying three sections of the virus that are crucial to human immune response -- a step that could lead to an accurate diagnostic kit. They have also found a way to rapidly -- and accurately -- screen blood samples for the virus, and plan to use it to test samples from animal species in hopes of figuring out the source, Bi says.

One of Bi's graduate students, Zhou Yongdong, explains that he is using genetic engineering techniques to manufacture three proteins that the virus uses to infect human cells. But such work came only after political and scientific obstacles were overcome.

Between cigarettes and gulps of wine, the U.S. CDC-trained Bi explains how his lab was stymied in its attempts to decipher the SARS crisis. In December, he learned that a strange outbreak was under way in the southernmost province of Guangdong. But local officials insisted to Bi's colleague, epidemiologist Liang Wannian, that "everything seemed OK. ... Keep the story silent," Bi recalled. "Local doctors were told, 'You can only report two cases -- not 20. Or the local economy will be hurt.'"

By early February, Liang went to Guangzhou, the largest city in Guangdong, and confirmed an epidemic was afoot. Bi and his colleagues set up a team to study the new disease, which Guangzhou doctors told them would not respond to antibiotics -- and, as such, must be viral.

"But there was a big problem," Bi said: He could obtain no patient blood, sputum or tissue samples.

"We were told, 'If you want samples from Guangzhou you must go through the Ministry of Health,'" Bi recalled, adding that his lab, which is part of the Chinese Centers for Disease Control, was warned that "we must be careful asking anything of local authorities. It's ridiculous! They said, 'You have to negotiate carefully with the local CDC.' I said, 'No way.'"

Weeks passed before the World Health Organization announced the presence of a new pneumonia disease in Vietnam and Hong Kong. Bi and his team noted that Guangzhou is just a short train ride from Hong Kong.

On Feb. 15 a minute sample arrived -- 50 microliters of scrapings from an infected lung. Dr. Hong Tao, the group's microscope expert, examined it and concluded the killer microbe was a bacterium that is common in China, chlamydia. For weeks, Hong would examine sample after sample, always reaching the same chlamydia conclusion. But it didn't make sense, Bi argued, because chlamydia can be killed by antibiotics -- and the new disease would not respond to the drugs.

So the team's influenza expert was sent to Guangzhou. "He gets there, and they told him, 'It must be chicken flu, because 100 percent of chick embryos died when we inoculated them with samples.'" But it turned out the eggs were put into an incubator that contained carbon dioxide -- and "'If you put yourself in a room filled with carbon dioxide, 100 percent of you will die!'" Bi quoted the flu expert's account. "He said there was no evidence the disease was avian flu."

In Guangzhou a doctor was watching doctors and nurses die of SARS, and he decided to send patient samples to a Hong Kong laboratory and to Bi without permission from the local CDC. On March 17, Bi opened a container with 30 samples from SARS patients and 30 more from patients in recovery. And when a pair of Guangzhou patients who were transferred to Beijing for treatment died in early March, their tissue and blood samples ended up in Bi's lab.

By March 19, Bi's lab had identified a microbe.

"So I believe we have a Nobel in our hands," he says, laughing. "We have the pathogen."

For days loud arguments raged in the halls, as Bi gathered more evidence that the pathogen was a virus, and Hong insisted that only chlamydia could be the culprit. Their disputes were being reported up the ladder of the Ministry of Health, to the highest political officials in this country, but only the chlamydia findings were reported to WHO and the Chinese people.

So Bi grew samples of his mystery pathogen from an acute patient's lung tissue, and combined it with antibodies from recovered SARS patients. He reasoned that the pathogens would get grabbed by the antibodies, and everything else would pass through.

He then set to work analyzing his pure pathogen sample. By then the U.S. CDC was saying the respiratory syndrome was caused by a new coronavirus; Bi wanted to genetically sequence the bug.

Finally, Hong saw the coronaviruses' distinct crown-like shapes under his microscope, and the fights between Bi and Hong stopped. In a matter of days the Chinese government admitted that the scope of the outbreak had been covered up, and the minister of health -- who had continuously supported Hong's theory on chlamydia -- was sacked.

Since then Bi has concentrated on determining the source of the virus. He recently figured out that the section of the virus recognized by the body's immune system bears less than 20 percent similarity to any known coronavirus, explaining why humans "have no immunological ability against it," he said.

Now the local CDC in Guangzhou is cooperating, tracking down animals in the city's wild animal market where more than 100 species are sold alive for human consumption. Blood samples from these animals are being delivered to Bi's lab, where they will be screened using his new diagnostic techniques.

Bi hopes he will soon find that an animal is the source of the emerging epidemic -- and that he will identify the species. "I just want to keep an attitude like a kid," he says of the weighty responsibility. "We don't care about money, fame. I'm just playing in the mud like a kid."